Method of producing racemic estradiol-3,17{62

ABSTRACT

A method of producing racemic estradiol-3,17 Beta wherein 6methoxytetralone is demethylated by hydrobromic acid in the medium of acetic acid while boiling, the resultant 6hydroxytetralone is reacted with vinylmagnesiumbromide to form into 1-vinyl-1,2,3,4-tetrahydronaphthalene-1,6-diol which is condensed with 2-methylcyclopentane-1,3-dione; the thus-obtained Delta 1,3,5(10),9(11)-8,14-seco-estratetraen-3-o1-14,17-dione is subjected to cyclization, the resulting Delta 1,3,5(10),8(9), 14(15)-estrapentaen-3-o1-17-one is hydrogenated into Delta 1,3,5(10),8(9)-estratetraen-3-o1-17-one then reduced by sodiumborohydride and the thus-produced Delta 1,3,5(10),8(9)estratetraene-3,17 Beta -diol is subjected to ionic reduction by triethylsilane and trifluoroacetic acid in the medium of an organic solvent followed by the isolation of the final product. The thus-obtained racemic estradiol-3,17 Beta finds application in medical practice as a pharmaceutical preparation in the treatment of genital disorders, and therapy of hormone-dependent tumors, as well as a component in contraceptive prescriptions.

United States Patent [191 Serebryakova et al.

[ Sept. 25, 1973 METHOD OF PRODUCING RACEMIC ESTRADIOL-3J7B Inventors:Tatyana Andreevna Serebryakova, ulitsa Mosfilmovskaya, 41, kv. 58;Ardalion Vladimirovich Zakharychev, ulitsa Zatonnaya, 9, korpus 5, kv.77; Margarita Alexandrovna Nekrasova, ulitsa Junnatov, 15, korpus B, kv.l0; Sofya Nikolaevna Ananchenko, Leninsky prospekt, 40, kv. 36; IgorVladimirovich Torgov, ulitsa Obrucheva, l6, kv. 34, all of Moscow,U.S.S.R.

Filed: Apr. 23, 1971 Appl. No.: 137,090

US. Cl 260/397.5, 260/397.45, 260/590,

260/621 Int. Cl. C07c 169/08 Field of Search Machine Searched SteroidsReferences Cited UNITED STATES PATENTS 5/1967 Windholz et a1 260/397.410/1969 Kuo et al. 260/397.l

3,501,509 3/1970 Kuo et al. 260/397.5

Primary ExaminerHenry A. French Attorney-Waters, Roditi, Schwartz &Nissen [57 ABSTRACT A method of producing racemic estradiol-3,l7Bwherein 6-methoxytetralone is demethylated by hydrobromic acid in themedium of acetic acid while boiling, the resultant -hydroxytetralone isreacted with vinylmagnesiumbromide to form intol-vinyll,2,3,4-tetrahydronaphthalene-1,6-diol which is condensed with2-methylcyclopentane-1 ,3-dione; the thusobtained N' 8, 14-seco-estratetraen-3-o l 14,17-dione is subjected to cyclization, theresulting A" -estrapentaen-3-ol-17-one is hydro genated into A-estratctraen-3-0l-l7-0ne then reduced by sodiumborohydride and thethus-produced A -estratetraene-3,l7B-diol is subjected to ionicreduction by triethylsilane and trifluoroacetic acid in the medium of anorganic solvent followed by the isolation of the final product.

The thus-obtained racemic estradiol-3,l7B finds application in medicalpractice as a pharmaceutical preparation in the treatment of genitaldisorders, and

therapy of hormone-dependent tumors, as well as a component incontraceptive prescriptions.

5 Claims, No Drawings METHOD OF PRODUCING RACEMIC ESTRADlOL-3,l7fi

The present invention relates generally to methods of producing steroidhormones, and more specifically to a method of producing racemicestradiol-3,17B which is used as a medicinal preparation for treatmentof genital disorders, and for therapy of hormonedependent tumors, aswell as a component in contraceptive prescriptions.

A method of producing racemic estradiol-3,l7B, is known wherein asolution of vinyl bromide is tetrahydrofuran is added to a suspension ofmetallic Mg in anhydrous tetrahydrofuran while cooling. Thereupon, thetemperature of the mixture is raised to 20C and it is boiled at 40C;then the mixture is diluted with ether, cooled and a solution of6-methoxytetralone in anhydrous tetrahydrofuran is added thereto. Themixture is stirred at 20C for 1.5 hours, and held for 12 hours at +2Cand during 2 hrs. After having been cooled down to +C the reaction massis poured into a mixture of ice and ammonium chloride, the product thusobtained is extracted with ether, the extract is washed with water,dried, and the solvent is distilled off to obtainl-vinyl-6-methoxytetralol-l. The l-vinyl-6- methoxytetralol-l iscondensed with Z-methylcyclopentane-l,3-dione by boiling in a methanolsolution in the presence of sodium methylate as a catalyst, followed byextraction of 3-methoxy-A 8,l4- secoestratetraene-l4-l7-dione, washingof the extract with a S-percent aqueous alkaline solution, evaporationof the solvent and crystallization. The product thus obtained issubjected to cyclization with toluenesulfonic acid by boiling inbenzene, followed by washing with water, evaporation of the solvent andcrystallization of the thus-obtained A -bisdehydroestrone methyl ether;alternatively, the cyclization process may be carried out by usingglacial acetic acid at room temperature with subsequent extraction ofthe final product, washing same with water, evaporation andcrystallization of A--bisdehydroestrone methyl ether.

The A8,]4-bisdehydroestrone methyl ether is subj'ected to hydrogenationin tetrahydrofuran in the presence of a palladium catalyst to obtain Adehydroestrone methyl ether which is reduced by alkali metals in liquidammonia at a temperature of 50 to -60C in tetrahydrofuran and ether,whereby estradiol-l7fl 3-methyl ether is produced.

The product thus obtained is oxidized with chromic anhydride inpyridine, whereupon the isolated estrone methyl ether is subjected todemethylation with pyridine bromohydrate at 220-230C to obtain estronewhich is then reduced with lithium aluminum hydride in anhydroustetrahydrofuran at C, followed by extraction of the end product,evaporation of the solvent and crystallization of the final product,viz., estradiol-3,l7fl. The yield is 12-14 wt.% when calculated foro-methoxytetralone (cf.USSR Author's Certificate No. 157056, journalKhimia prirodnykh soedineniy" (Chemistry of Natural Compounds) (3), 172,1965).

The above-discussed method, however, suffers from a number ofdisadvantages such as low yield of the final product, complicatedtechnological process and equipment. Thus, the stage of demethylationwith pyridine bromohydrate takes place at elevated temperatures(220-230C) which involvesthe use of appropriate equipment and apparatus.Besides, the maximum percentage of losses in the yield of the finalproduct occurs at that stage.

Furthermore, the stage of reduction with alkali metals in liquid ammoniaat -50 to -60C requires special refrigeration equipment, largeconsumption of highpurity ammonia and inflammable solvents, such asether and tetrahydrofuran, the yield at that stage being moderateamounting to 50 wt.%.

Another method of producing racemic estradiol-3,17B is known wherein aheterogeneous mixture of pyridine bromohydrate and 6-methoxytetralone isheated at 220-225C, then cooled, dissolved in a 10- percent hydrochloricacid and extracted with ether, whereupon the ethereal extract is washedwith a saturated aqueous solution of sodium bicarbonate, dried, thesolvent is distilled off and the residue is crystallized from water withthe addition of sodium hydrosulfite. The thus-obtained6-hydroxytetralone is treated with vinylmagnesiumbromide in a solutionof anhydrous tetrahydrofuran and ether at -20C, then is held for 12hours at 0C and boiled for 2 hours at 40C. Then the reaction mass iscooled down to +lOC and poured into a mixture of ice and ammoniumchloride, the organic layer is drawn off and the aqueous layer isextracted several times with ether. The extract having been washed,dried and concentrated the residue is washed with cold ether to obtainl-vinyl-l,2,3,4- tetrahydronaphthalene-l,6-diol which is then condensedwith 2-methylcyclopentane-l,3-dione in the presence oftrimethylbenzylammonium, hydroxide as a catalyst while boiling intertiary butanol for 1 hour. Then the obtained product is extracted withether, the extract is washed with a saturated solution of sodiumbicarbonate, dried, the solvent is evaporated the residue is washed withether to A" '"-8,14-secoestratetraen-3-ol-14,17-dione. The resultantproduct is treated with hydrochloric acid at a ratio of 1:1 intetrahydrofuran at 20C for 12 hours, with subsequent extraction withether, washing with a saturated aqueous solution of sodium bicarbonateand then with water, drying, evaporation of the solvent andcrystallization of the obtained product, viz., A-"'-estrapentaen-3-ol-l7-one.

The isolated product is hydrogenated with gaseous hydrogen in a solutionof tetrahydrofuran over a 10- percent palladium on calcium carbonate.Upon filtration, solvent evaporation and crystallization of the residue,an intermediate product is obtained, viz., A -estratetraem 3-ol-l7-one;which is then isomerized with hydrochloric acid (1:1) in tetrahydrofuransolution for 1 hour. The reaction mass is neutralized with a saturatedaqueous solution of sodium bicarbonate, extracted with chloroform,washed with water, dried concentrated and crystallized from methanol toobtain A" -estratetraen-3-ol-l7-one. The product obtained ishydrogenated with gaseous hydrogen in tetrahydrofuran over IO-percentpalladium on calcium carbonate, the catalyst is filtrated off, thesolvent is evaporated the residue is crystallized to obtain racemicestrone. Further, estrone is reduced with sodium borohydride or lithiumaluminum hydride and, by resorting to conventional techniques, racemicestradiol-3,l7fi is isolated. The yield of the final product is 4-5 wt.%as calculated for 6-methoxytetralone /cf.Steroids, 4(1), 31 (l964)/.

A disadvantage inherent in the above method is the low yield of thefinal product. Another disadvantage of this method resides in that thestage of demethylation with pyridine bromohydrate is carried out at ahigh temperature (220C) which involves special equipment, the yield atthat stage being unstable. Besides, when utilizing starting substancesin amounts exceeding 5 g the yield decreases and cannot be duplicated sothat the process is difficult to carry out under plantproductionconditions. The stage of producingl-vinyll,2,3,4,-tetrahydronaphthalene-l ,6-diol occurs at a lowtemperature its yield being not in excess of 70 wt.%.

The stage of acid isomerization of estratetraen-3-ol-l7-one into A"-estratetraen- 3-ol-l7-one is difficult due to nearly equal solubilityof both; thus, to isolate the latter a thorough triple crystallizationis needed till a constant melting point of the product is obtained. Theyield at that stage is about 36 wt.%. Apart from everything discussedabove, one more disadvantage of the method lies in the necessity of thestage of catalytic hydrogenation, this stage being inadequatelystereospecific, and the yield of estrone being as low as 50-55 wt.%.

It is a primary object of the present invention to increase the yield ofthe final product.

It is another object of the present invention to simplify the process.

Said primary and other objects of the invention have been attained dueto the provision of a method of producing racemic estradiol-3,l 73 bydemethylation of 6- methoxytetralone; interaction of the resultant 6-hydroxytetralone with vinylmagnesiumbromide; condensation of thethus-formed l-vinyl-l,2,3,4- tetrahydronaphthalene-l,6-diol with2-methylcyclopentane-l ,3-dione; cyclization of the obtained A'"-8,l4-seco-estratetraen-3-ol-l4,17-dione; hydrogenation of the aboveproduct; and reduction of A -estratetraen-3-ol-l7-one resulting from theabove hydrogenation, into the final product, in which method, accordingto the invention, demethylation of 6- methoxytetralone is effected byhydrobromic acid in boiling acetic acid, whereas the process ofreduction of A" -estratetraend-ol-l7-0ne is carried out by sodiumborohydride with subsequent ionic reduction of the thus-obtained A"''--estratetraene-3,l7B-diol by triethylsilane and trifluoroacetic acidin an organic solvent and isolation of the final product.

It is expedient that benzene be used as an organic solvent in the ionicreduction process.

It is preferable to carry out the ionic reduction process at a molarratio between A -estratetraene- 3,17 -diol triethylsilane andtrifluoroacetic acid equal to 1:20:20.

To increase the yield of the end product the reaction of 6-oxytetralonewith vinylmagnesiumbromide proceeds at l8-20C. The final product ispreferably isolated by extraction with benzene from the reaction mass,concentrating the resulting extract; treatment with sodium borohydridein methanol at 40-45C, then with acetic acid when cooled and separationof the crystallized final product.

The herein-proposed method is carried out as follows.

6-methoxytetralone is demethylated by being boiled in a mixture ofglacial acetic acid with 48-percent hydrobromic acid. The resultingproduct is extracted with ethyl acetate, washed and concentrated toobtain 6- hydroxytetralone which is treated with vinylmagnesiumbromidein a solution of tetrahydrofuran and ether at 20C and then boiling themixture at 40C. Then the reaction mass is cooled down to +l0C and pouredinto a mixture of ice and ammonium chloride, whereupon the resultantl-vinyl-l,2,3,4-tetrahydronaphthalene- 1,6-diol is extracted with etherand the solvent is distilled off.

The thus-produced l-vinyl-l,2,3,4-tetrahydronaphthalene-l,6-diol iscondensed with 2-methylcyclopentane-l ,3-dione and the resultant A"-"-8,l4-secoestratetraen-3-ol-l4,l7-dione is subjected to cyclizationfollowed by hydrogenation and isolation of A -estratetraen-S-ol-l 7-one.

The isolated product is reduced with sodium borohydride in a S-percentmethanol solution of potassium hydroxide at 0+5C, the mixture isneutralized and extracted with ethyl acetate, the solvent is evaporated,and the residue is crystallized to obtain A- estratetraene-3,l7B-diol.The latter is subjected to ionic reduction with a mixture oftrifluoroacetic acid and triethylsilane in an organic solvent (methylenechloride, benzene, etc.) at 20C.

The reaction mixture is poured by portions into ice, extracted withbenzene, the extract is washed with a 5- percent aqueous solution ofsodium bicarbonate and with water and concentrated. The residue istreated with sodium borohydride in methanol at 40C, the mixture ispoured into a S-percent acetic acid solution while cooling and the thuscrystallized racemic estradoil-3,l7fi is filtered off.

The yield of the final product is 30 wt.% as calculated for6-methoxytetralone.

The proposed method enables the technological process to be simplified.The stage of demethylation proceeds in a homogeneous medium which makesit possible to increase the yield to 98 wt.% at that stage and dispensewith complicated technological equipment and apparatus. The stage ofproducing l-vinyl-l,2,3,4- tetrahydronaphthalene-l,6-diol takes place atroom temperature. Instead of the isomerization stage which gives but alow yeild, and the stage of catalytic hydrogenation made use of in theknown method, the method of the invention employs the stage of ionicreduction with trifluoroacetic acid in a mixture with triethylsilane.

Due to simplification of a number of technological operations the yieldof the final product is increased to 30 wt.% as calculated for6-methoxytetralone, as compared to 5-20 wt.% in the heretofore knownmethods.

To promote understanding of the present invention the following is anexemplary embodiment thereof illustrating the production of racemicestradiol-3,l 73 by the method of the invention.

A solution of 62 g of 6-methoxytetralone in a mixture of 435 ml ofglacial acetic acid and ml of 48- percent hydrobromic acid, is boiledfor 10 hours. Then the solution is concentrated in vacuo to one-third ofthe initial volume and poured into 1.5 litres of water, whereupon theobtained product is extracted with ethyl acetate. The extract is washedwith a saturated aqueous solution of sodium bicarbonate and with water,dried and evaporated. The residue is washed with cold water andair-dried to obtain 56.5 g of 6-hydroxytetralone with a m.p. ofl49-l53C, the yield thereof being 98 wt.% of the theoretical.

To a mixture of 36.5 g of metallic magnesium chips and 150 ml ofanhydrous tetrahydrofuran a few drops of methyl bromide are addedwhereupon the mixture is heated till the reaction begins. Then, whilestirring and cooling down to +5C, 229 g of vinylbromide dissolved in 450ml of anhydrous tetrahydrofuran are added dropwise to the mixture,maintaining its slow boiling. This done, the temperature of the reactionmixture is elevated first to 20C, whereupon the mixture is kept boilingfor 1 hour at +40C. Then the mixture is diluted with 500 ml of absoluteether followed by the dropwise addition at 20C of 56.5 g of6-oxytetralone in anhydrous tetrahydrofuran under vigorous stirring. Themixture obtained is diluted with 200 ml of anhydrous tetrahydrofuran and100 ml of absolute ether, allowed to stand for 12 hours and boiled for 2hours. The resultant reaction mixture is cooled down to +l0C and pouredby portions into a mixture of 2 kg of ice and 100 g of ammoniumchloride. The organic layer is separated, while the aqueous one isthrice extracted with ether (about 2 liters). The combined extract iswashed with a saturated sodium hyposulfhite solution and evaporated invacuo at 30-35C. The residue is washed with cold ether to obtain 60 g ofl-vinyll,2,3,4-tetrahydronaphthalene-l,6-diol, m.p. 200C withdecomposition, the yield being 90 wt.% of the theoretical.

To 800 mg of the thus-obtained 1-vinyl-l,2,3,4-tetrahydronaphthalene-l,6-diol and 800 mg of 2- methylcyclopentane-l,3-dione dissolved in 7 ml of tertbutanol, is added 1 ml of a saturatedalcoholic solution of trimethylbenzyl ammonium hydroxide resulting frommixing alcoholic solutions of equimolar quantities oftrimethylbenzylammoniumhydrochloride and potassium hydroxide, followedby filtering off the potassium chloride and cencentrating the solvent toa volume of 1 ml. The reaction mixture is boiled 1 hour, diluted withhalf-volume of ether, washed with a saturated sodium bicarbonatesolution and water, dried and evaporated. The residue is washed with.cold ether to obtain 970 mg of A-"" "-8,l4-seco-estratetraen-3-01-14,17-dione, m.p. of 122-l24C, the yield being 80 wt.% of thetheoretical.

970 mg of the thus-obtained A"-"'"-8,l4-secoestratetraen-3-ol-l4,l7-dione are dissolved in 14 ml oftetrahydrofuran containing 3 ml of hydrochloric acid (1:1), and allowedto stand for 12 hours at C, then extracted with ether. The extract iswashed with a saturated aqueous solution of sodium bicarbonate and withwater, dried with anhydrous magnesium sulfate and evaporated. Uponcrystallization of the residue from a methanolethyl acetate mixture(1:1), 750 mg of A -estrapentaen-3-ol-17-one, m.p. of 2l3-2l8C wereobtained, the yield being 82 wt.% of the theoretica].

750 mg of A'"-" f -estrapentaen-S-ol-l7-one dissolved in ml oftetrahydrofuran, are hydrogenated per double bond over l0-percentpalladium on calcium carbonate. The solution is filtered from thecatalyst, the filtrate is evaporated and the residue is crystallizedfrom methanol to obtain 630 mg of A -estratetraen-ii-oll7-one, m.p. of242246C, with a yeild of 83 wt.% of the theoretical.

To a solution of 630 mg of A--estratetraen-3-oll7-one in 5 ml of aS-percent methanol solution of potassium hydroxide is added dropwise asolution of 0.2 g of sodium borohydride in 3 ml of a S-percent metha nolsolution of potassium hydroxide. The resulting solution is stirred for3.5 hours at 0+5C. Then the mixture is poured into water, neutralizedwith 2-percent hydrochloric acid, extracted with ether and then withethyl acetate. The extract is washed with water, dried with anhydrousmagnesium sulfate and evaporated in vacuo. The residue is crystallizedfrom 90-percent aqueous methanol to obtain 500 mg of A" -estratetraene-3,17B-diol, m.p. of l20/205-2l2C, the yield being wt.% of thetheoretical.

To 500 mg of A" -estratetraene-3,l7B-diol dissolved in 25 ml of absolutebenzene 5 ml of triethylsilane and 2.4 ml of trifluoroacetic acid areadded at 30C and the mixture is allowed to stand for 3 hours at 20C.Then the mixture is poured dropwise onto ice and extracted with benzene.The extract is washed with a S-percent aqueous solution of sodiumbicarbonate, then with water and evaporated. To the residue dissolved in40 ml of methanol, 1 g of sodium borohydride in 24 ml of methanol isadded and the mixture is stirred 2 hours at 4045C. The mixture is pouredinto 24 ml of a S-percent acetic acid (pl-l=3.5) with ice-cooling.

The precipitate is filtered, washed with water and air-' Itetrahydronapthalene-l,6-diol, (3) condensing said 1-vinyl-l,2,3,4-tetrahydronaphthalene-l,6diol with 2-methyl-cyclopentene-l,3-dione to form A"8,14-seco-estratetraen-3-ol-14,17-dione, (4) cyclizingestrapentaene-3-ol-l7-one to form A estratetraen-3-ol-l7-one, (6)reducing said ri estratetraen-3-oll 7-one to form A"-estratetraene-3,l7B-diol, (7) ionically reducing said A"-estratetraene-3 l 7fl-diol with triethylsilane and trifluoroacetic acidin an organic solvent to form estradiol -3,l7fl and (8) isolating saidestradiol-3,l7B.

2. A method according to claim 1 wherein the organic solvent in step (7)is benzene.

3. A method according to claim 1 wherein the molar ratio of A"-estratetraene-3,l7B-diol to triethylsilane to trifluoroacetic acid is1:20:20.

4. A method according to claim 11 wherein step (2) is carried out atl8-20C.

5. A method according to claim 11 wherein step (8) comprises extractingsaid estradiol-3,l7B from the reaction mixture with benzene, evaporatingthe benzene extract to form a residue, treating said residue with sodiumborohydride in methanol at 4045 C. and then with acetic acid withcooling, and separating the crystallized estradiol-3,17B.

2. A method according to claim 1 wherein the organic solvent in step (7)is benzene.
 3. A method according to claim 1 wherein the molar ratio ofDelta 1,3,5(10),8(9)-estratetraene-3,17 Beta -diol to triethylsilane totrifluoroacetic acid is 1:20:20.
 4. A method according to claim 1wherein step (2) is carried out at 18*-20*C.
 5. A method according toclaim 1 wherein step (8) comprises extracting said estradiol-3,17 Betafrom the reaction mixture with benzene, evaporating the benzene extractto form a residue, treating said residue with sodium borohydride inmethanol at 40*-45* C. and then with acetic acid with cooling, andseparating the crystallized estradiol-3,17 Beta .